Practice Essentials

B virus, whose scientific name is macacine herpesvirus 1 (McHV-1), is commonly referred to as herpes B. Other terms include simian herpes, monkey B virus, herpesvirus simiae, and herpesvirus B. B virus produces infection in several species of Old World macaque and cynomolgus primates. Human contact with macaque and cynomolgus species may occur during laboratory work with captive monkeys. In addition, the risk of nonoccupational human encounters with Old World monkeys may be increasing with the popularity of travel to developing and exotic locales.

Primates with B virus infection are often asymptomatic, but B virus, in rare cases, can produce life-threatening disease in humans with mucosal or percutaneous contact (bite, scratch, splash, or needlestick) to primate saliva or other body fluids. Approximately 70% of untreated infections result in fatal encephalitis in humans.

Human-to-human transmission is unlikely, but antibody seroconversion has been documented in one case, in the wife of an infected animal handler after using an ointment on her skin with which she treated his wounds; she herself did not develop clinical illness.
[1]

Contact with primate body fluids, however healthy-appearing the animal, must not be ignored. Exposed wounds or mucosa should be immediately washed with soap and water, followed by evaluation for prophylactic antiviral therapy. While laboratory protocols for handling of primates and occupational exposures exist, the general public and many clinicians remain unaware of B virus.

Prompt consultation with public health officials or an infectious disease specialist may facilitate assessment for antiviral prophylaxis of primate exposures.

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Background

Macacine herpesvirus 1 (McHV-1) is an alphaherpesvirus that is enzootic to the rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) members of the macaque genus, Macaca (as seen in the image below). Among the nonhuman-primate herpesviruses, only B virus is known to cause disease in humans. Its medical importance is its propensity to cause devastating central nervous system (CNS) infection after contact of infected saliva with mucosal fluids, wounds, or tissues. This fact is known in the research community, and there are published protocols for preventing exposures, as well as postexposure prophylaxis. While many clinicians and the lay public are unaware of the risk, opportunities for nonoccupational human encounters with Old World monkeys are increasing.

This is a photo of long-tailed macaques socializing in the wild. The long-tailed macaque, Macaca fascicularis, is a major reservoir for the herpes B virus. (Photo courtesy of Carel van Schaik)

These primates may be found in close proximity to human habitation in the Caribbean and other parts of the world. Humans may be exposed to B virus during international travel and during travel to US territories. Originally imported for clinical research, some animals escaped, and free-ranging populations of rhesus and patas monkeys now inhabit rural and urban areas of Puerto Rico, as well as surrounding islands. A rhesus monkey colony has been established since the 1930s in Silver Springs State Park, Florida, where they were imported in the 1930s to boost tourism. Both populations have been observed to have antibodies to B virus and to shed reactivated virus in saliva.
[2]

Similar to human herpes simplex virus (HSV), B virus belongs to the family Herpesviridae, subfamily Alphaherpesvirinae, genus Simplexvirus. It is properly referred to by its current taxonomic name, macacine herpesvirus 1 (McHV-1).
[3] Adding confusion, it may also be identified in literature as macacine alphaherpesvirus 1 or under an older taxonomy, cercopithecine herpesvirus 1. The term herpes B was coined in 1934 from the initials of the first human case, which was described in detail by Sabin and Wright; "Dr. W.B." was a 29-year-old researcher who developed fatal meningoencephalitis and transverse myelitis following a bite on the hand from a seemingly healthy rhesus monkey.
[4]

B virus contains double-stranded linear DNA and has a molecular weight of approximately 110 megadaltons (approximately 162 kilobase pairs). It shares about 50% of its genes with human herpes simplexviruses and expresses the same glycoprotein D (HSV-1 gD) binding proteins. However, infection of human cells may take different routes and is under study. Unlike human herpes simplexviruses, B virus gD does not bind herpesvirus entry mediator (HVEM) proteins, but fuses with human nectin-1, nectin-2, and, possibly, other surface proteins.
[5, 6, 7]

Most macaques infected with B virus are asymptomatic. When symptoms do occur, they are very similar to those caused by HSV infection in humans. The most obvious manifestation of B virus infection is the presence of fluid-filled vesicles on the back of the tongue, lips, and elsewhere in the mouth; occasionally, the vesicles appear on the lips. When the vesicles rupture, they often give rise to ulcers and necrotic scabs, which may lead to secondary bacterial and fungal infections. Scabs typically heal within 7-14 days. Conjunctivitis of varying severity is another common symptom.

In rare instances, B virus may cause systemic illness in macaques, including the occurrence of ulcerative lesions in the mouth, esophagus, and stomach and necrosis of the liver, spleen, and adrenal glands. While the virus is shed in saliva and in conjunctival, nasal, and genital fluids, viremia is uncommon.
[8, 9, 2] Similar to human HSV infection, after acute infection, B virus remains latent in the ganglia of trigeminal and lumbosacral nerve roots and may reactivate intermittently owing to stress or illness. The animals commonly transmit infection to each other via shared ocular, nasopharyngeal, and venereal fluids.

Members of the genus Macaca (>16 species) are natural hosts of B virus, and almost all of these hosts naturally exist in Asia. Both wild and captive macaque populations generally exhibit high rates of herpes B virus infection, but most individuals exhibit few or no symptoms of infection. The strongest evidence for this pattern of high prevalence and mild infection comes from the rhesus, Japanese, and long-tailed (or cynomolgus) macaques, all of which are very closely related phylogenetically. In wild and semi–free-ranging populations of long-tailed and rhesus macaques, seroprevalence rates (or prevalence of serum-detected herpes B virus–induced antibodies) typically exceed 70%.

Captivity likely affects the risk of shedding, which is expected to be higher in stressed, breeding, or immunocompromised animals. In surveys of captive populations, 80%-100% of adults are seropositive for B virus.

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Pathophysiology

In humans, B virus produces local infection at the inoculation site, with concomitant local and regional inflammatory changes. Vesicular eruption, local pruritus, numbness, or tingling may occur. Regional lymphadenitis and lymphangitis may also occur, and lymph nodes draining the entry site may demonstrate hemorrhage and focal necrosis on histopathology.

Within 4 weeks of inoculation, the virus progresses via peripheral nerves to the CNS, causing local and systemic inflammation and neurologic dysfunction along the way. Beginning with peripheral paresthesia at the site of infection, symptoms progress centrally to produce global CNS pathology, including meningitis and encephalitis, cranial nerve palsies, and brain stem impairment.
[10, 11, 1] Systemic symptoms with fevers, rigors, conjunctivitis, sinusitis, and myalgias occur and may be the only manifestation in some cases. At least one case in which disease occurred years after exposure has been reported, suggesting that herpes B virus might be able to become latent and reactivate in humans.
[12] Self-limited aseptic meningitis has been reported, but almost all cases produce substantial morbidity and mortality.

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Epidemiology

Frequency

United States

Of roughly 45 well-documented cases of B virus infection in humans, two thirds occurred in the United States and the others were reported in Canada and Great Britain. Most of the well-documented human cases occurred in the 1950s and 1960s, when large numbers of rhesus macaques were used in the production and testing of poliomyelitis vaccines. In the late 1980s, several cases in Pensacola, Florida and Kalamazoo, Michigan, refocused attention on B virus, and several other cases have since been documented. The increase coincides with an increased use of macaques in human immunodeficiency virus (HIV) research.

International

Reports of human B virus infection from countries where macaques are prevalent and commonly interact with humans are uncommon. Whether the absence of these reports is due to the limited availability of B virus diagnostic facilities (ie, actual cases not identified) or if some other factors are responsible (eg, different animal-handling procedures) is unclear. B virus has been identified in wild macaque species in Asia and Southeast Asia. Increasing opportunities for human B virus infections is a concern because of increasing human encroachment upon natural habitats and increasingly adventurous travel.

Age

The average age of persons who develop B virus infection reflects the demographics of individuals involved with the care of primate hosts in research laboratories.

Transmission

Information regarding the epidemiology and transmission of B virus in primates is vital in order to understand how to prevent this high-mortality infection.

Macaques transmit B virus to each other through oral, ocular, or genital contact of mucous membranes or lesioned skin. B virus can be shed asymptomatically, including through bodily fluids (eg, semen, mother's milk, saliva, perhaps even in aerosol form). The animal stools could also conceivably transmit the virus. In captive macaques, transmission may often occur during routine colony management protocols involving tube sharing, common instrumentation, or contaminated gloves. Animals usually become infected as juveniles, at the onset of sexual activity; however, younger animals can become infected through contact with another virus-shedding animal. For example, a nursing mother has repeated opportunities to transmit the virus in buccal or conjunctival fluids to a nursing infant during grooming.

Conclusively determining transmission pathways may not be possible because most human cases of B virus infection involve individuals who regularly work with monkeys, thus providing many potential means of exposure. Suspected transmission modes include monkey bites, monkey scratches, or cage scratches; direct contamination of a preexisting wound with macaque saliva; respiratory exposure to aerosol macaque saliva; mucosal splash exposure; cuts sustained from culture bottles containing macaque kidney cells; needle-stick injuries following needle use in macaques; and cleaning a rhesus macaque skull without gloves. In addition, one apparent case of human-to-human herpes B virus transmission involved a woman with dermatitis on her finger; she touched her husband's herpetiform lesion (resulting from a monkey bite).
[10]

Given the myriad potential transmission pathways and abundance of macaques in contact with people, the fact that relatively few documented cases of B virus infection occur in humans may seem surprising. Nevertheless, although most macaques test positive for B virus antibodies, only a small percentage (ie, 0-2%) shed the virus at any given time. In most animals, the virus is latent in the trigeminal ganglia and becomes reactivated only when the macaque experiences psychological stress, pharmacological stress, or diminished immunocompetence.
[12]

The widely observed pattern of increasing frequency with age suggests that horizontal transmission is far more common than vertical transmission (ie, mother to offspring). Whether this horizontal transmission occurs most commonly via oral or genital contact, including sexual behavior, is unresolved.

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Prognosis

Historically, human B virus encephalitis carries a case-fatality rate of up to 80%, a rate similar to that of untreated HSV encephalitis. Most individuals with encephalitis succumb to the infection despite antiviral therapy.

As with HSV encephalitis, many survivors of B virus infection have substantial residual neurologic deficits.

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Patient Education

There is currently no commercially available vaccine against B virus.

All workers who handle macaque and cynomolgus monkeys should be aware of the risk, preventive procedures, and postexposure prophylaxis protocols for B virus infection. Some percentage of captive populations may be expected to be shedding the virus at any point in time.

Known habitats for macaque and cynomolgus monkeys include Asia, Southeast Asia, Silver Springs State Park in Florida, and Puerto Rico.

Travelers to rural and developing areas that these primates may inhabit should be aware of the risk posed by contact with primates and other animals and should be counseled to avoid feeding or touching them. In addition to pre-exposure prophylaxis against rabies, travelers should consider access to healthcare and local availability of postexposure antivirals for a monkey bite. The prospect of B virus infection may diminish the allure of photographs with these animals, regardless of the social media impact. Avoidance of contact is entirely effective for preventing B virus infection.
[2, 1, 13]

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Contributor Information and Disclosures

Author

Sandra G Gompf, MD, FACP, FIDSA Associate Professor of Infectious Diseases and International Medicine, University of South Florida College of Medicine; Chief, Infectious Diseases Section, Director, Occupational Health and Infection Control Programs, James A Haley Veterans Hospital